Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding, and phosphorylation

Citation
D. Szczesna et al., Familial hypertrophic cardiomyopathy mutations in the regulatory light chains of myosin affect their structure, Ca2+ binding, and phosphorylation, J BIOL CHEM, 276(10), 2001, pp. 7086-7092
Citations number
45
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
276
Issue
10
Year of publication
2001
Pages
7086 - 7092
Database
ISI
SICI code
0021-9258(20010309)276:10<7086:FHCMIT>2.0.ZU;2-Z
Abstract
The effect of the familial hypertrophic cardiomyopathy mutations, A13T, F18 L, E22K, R58Q, and P95A, found in the regulatory light chains of human card iac myosin has been investigated. The results demonstrate that E22K and R58 Q, located in the immediate extension of the helices flanking the regulator y light chain Ca2+ binding site, had dramatically altered Ca2+ binding prop erties. The K-Ca value for E22K was decreased by similar to 17-fold compare d with the wild-type light chain, and the R58Q mutant did not bind Ca2+. In terestingly, Ca2+ binding to the R58Q mutant was restored upon phosphorylat ion, whereas the E22K mutant could not be phosphorylated, In addition, the alpha -helical content of phosphorylated R58Q greatly increased with Ca2+ b inding. The A13T mutation, located near the phosphorylation site (Ser-15) o f the human cardiac regulatory light chain, had 3-fold lower K-Ca than wild -type light chain, whereas phosphorylation of this mutant increased the Ca2 + affinity 6-fold. Whereas phosphorylation of wildtype light chain decrease d its Ca2+ affinity, the opposite was true for A13T. The alpha -helical con tent of the A13T mutant returned to the level of wild-type light chain upon phosphorylation, The phosphorylation and Ca2+ binding properties of the re gulatory light chain of human cardiac myosin are important for physiologica l function, and alteration any of these could contribute to the development of hypertrophic cardiomyopathy.